Methods and Preparations For Curing Clinically Ill Patients

ABSTRACT

This invention relates to a life saving medicament for critically ill patients and a method of treatment. The composition is a pharmaceutically effective amount of a blood glucose regulator which is used to control the blood glucose level.

CROSS REFERENCE TO RELATED APPLICATIONS

This application is a continuation of U.S. application Ser. No.09/853,193 filed May 11, 2001 (allowed May 22, 2008) which is acontinuation of International Application No. PCT/DK01/00287 filed Apr.30, 2001 and claims priority under 35 U.S.C. 119 of Danish ApplicationNo. PA 2001 00604 filed Apr. 15, 2001; Pa 2001 00605 filed Apr. 16, 2001and British Application No. 0010856.3 filed May 5, 2000, the contents ofwhich are fully incorporated herein by reference.

FIELD OF THE INVENTION

The present invention relates to a novel the use of blood glucoseregulators, and a novel method of treating a clinically ill patient.Furthermore, the present invention relates to advertising media andmaterial and information media and material like giving informationabout the novel utilities, indications and actions of these medicamentsand to a method of selling these medicaments by giving information abouttheir novel utilities, indications and actions.

BACKGROUND

A specific type of polyneuropathy develops in patients that are treatedwithin an intensive care unit (hereinafter also designated ICU) forseveral days to weeks and this for a variety of primary injuries orillnesses. This polyneuropathy, known as “Critical IllnessPolyneuropathy” (hereinafter also designated CIPNP) occurs in about 70%of patients who have the systemic inflammatory response syndrome (SIRS)(Zochodne D W et al. 1987 Polyneuropathy associated with criticalillness: a complication of sepsis and multiple organ failure. Brain,110: 819-842); (Leijten F S S & De Weerdt A W 1994 Critical illnesspolyneuropathy: a review of the literature, definition andpathophysiology. Clinical Neurology and Neurosurgery, 96: 10-19).However, clinical signs are often absent and it remains an occultproblem in many ICUs worldwide. Nonetheless, it is an important clinicalentity as it (is) a frequent cause of difficulty to wean patients fromthe ventilator and it leads to problems with rehabilitation after theacute illness has been treated and cured.

When CIPNP is severe enough, it causes limb weakness and reduced tendonreflexes. Sensory impairment follows but is difficult to test in ICUpatients. Electrophysiological examination (EMG) is necessary toestablish the diagnosis (Bolton C F. 1999 Acute Weakness. In: OxfordTextbook of Critical Care; Eds. Webb A R, Shapiro M J, Singer M, Suter PM; Oxford Medical Publications, Oxford UK; pp. 490-495). Thisexamination will reveal a primary axonal degeneration of first motor andthen sensory fibers. Phrenic nerves are often involved. Acute andchronic denervation has been confirmed in muscle biopsies of thiscondition. If the underlying condition (sepsis or SIRS) can besuccessfully treated, recovery from and/or prevention of the CIPNP canbe expected. This will occur in a matter of weeks in mild cases and inmonths in more severe cases. In other words, the presence of CIPNP candelay the weaning and rehabilitation for weeks or months.

The pathophysiology of this type of neuropathy remains unknown (Bolton CF 1996 Sepsis and the systemic inflammatory response syndrome:neuromuscular manifestations. Crit Care Med. 24: 1408-1416). It has beenspeculated to be directly related to sepsis and its mediators. Indeed,cytokines released in sepsis have histamine-like properties which mayincrease microvascular permeability. The resulting endoneural edemacould induce hypoxia, resulting in severe energy deficits and herebyprimary axonal degeneration. Alternatively, it has been suggested thatcytokines may have a direct cytotoxic effect on the neurons.Contributing factors to disturbed microcirculation are the use ofneuromuscular blocking agents and steroids. Moreover, a role foraminoglucosides in inducing toxicity and CIPNP has been suggested.However, there is still no statistical proof for any of these mechanismsin being a true causal factor in the pathogenesis of CIPNP.

Although polyneuropathy of critical illness was first described in 1985by three different investigators, one Canadian, one American, and oneFrench, to date there is no effective treatment to prevent or stopCritical Illness Polyneuropathy.

To date the current standard of practice of care, especially ofcritically ill patients, was that within the settings of good clinicalICU practice, blood glucose levels are allowed to increase as high as to250 mg/dL or there above. The reason for this permissive attitude is thethought that high levels of blood glucose are part of the adaptivestress responses, and thus do not require treatment unless extremelyelevated (Mizock B A. Am J Med 1995; 98: 75-84). Also, relativehypoglycaemia during stress is thought to be potentially deleterious forthe immune system and for healing (Mizock B A. Am J Med 1995; 98:75-84).

BRIEF SUMMARY OF THE INVENTION

This invention was based in part on the discovery that critical illnessin a patient and/or CIPNP can be prevented, treated or cured, at leastto a certain extent, by strictly controlling glucose metabolism duringsaid critical illness by applying intensive treatment with a bloodglucose regulator, for example, insulin treatment, with clamping ofblood glucose levels within a range where the lower limit can beselected to be about 60, about 70 or about 80 mg/dL and the upper limitcan be selected to be about 110, about 120 or about 130 mg/dL, morespecifically to the normal range (i.e., from about 80 to about 110mg/dL). The skilled art worker, for example, the physician, will be ableto decide exactly which upper and lower limits to use. Alternatively,the range is from about 60 to about 130, preferably, from about 70 toabout 120, more preferred, from about 80 to about 110 mg/dL.

This invention demonstrates that clamping of blood glucose levels withinthe above range, for example, within normal limits (about 80 to about110 mg/dL) in a critically ill patient or in a chronic ill patient canbe used to significantly reduce the incidence of critical illness in apatient and/or CIPNP and to lengthen the time free of critical illnessin a patient and/or CIPNP in a patient that do develop this problem.

In the illustrative embodiments of present invention, blood glucoselevels were controlled by insulin treatment. However after thisinvention, it will be clear for the man skilled in the art that alsoactive insulin derivatives and its physiologically tolerated salts andother blood glucose regulators can be used to obtain the same outcome.

Furthermore, it will be clear for the man skilled in the art, thatcompounds of the group of biologically active substances having insulinreleasing action can be used to treat critical illness in a patientand/or Critical Illness Polyneuropathy or to manufacture a medicine totreat critical illness in a patient and/or Critical IllnessPolyneuropathy. Such compound with an activity of promoting thesecretion of insulin were already well disclosed before the moment ofthis invention such as the Islets-Activating Proteins (Ui; Michio et al.U.S. Pat. No. 5,000,953, 19 Mar. 1991) and the glucagon-like peptides(Habener; Joel F. Newton Highlands, Mass. U.S. Pat. No. 5,614,492, 25Mar. 1997).

Furthermore, it will be clear for the man skilled in the art, thatcompounds of the group of compounds that stimulate signal transductionmediated by an insulin receptor type tyrosine kinase in a cell can beused to treat or to manufacture a medicine to treat critical illness ina patient and/or Critical Illness Polyneuropathy. It was well knownbefore the date of this invention that insulin binding to the insulinreceptor triggers a variety of metabolic and growth promoting effects.Metabolic effects include glucose transport, biosynthesis of glycogenand fats, inhibition of triglyceride breakdown, and growth promotingeffects include DNA synthesis, cell division and differentiation. It isknown that some of these biological effects of insulin can be mimickedby vanadium salts such as vanadates and pervanadates. However, thisclass of compounds appears to inhibit phosphotyrosine phosphatasesgenerally, and are potentially toxic because they contain heavy metal(U.S. Pat. No. 5,155,031; Fantus et al., 1989, Biochem., 28:8864-71;Swarup et al., 1982, Biochem. Biophys. Res. Commun. 107:1104-9).Moreover, it had been already demonstrated (LAMMERS REINER et al. 19Jan. 1999, U.S. Pat. No. 5,861,266 & WO 9523217) that certainprotein-tyrosine phosphatases (PTP's), in particular, RPTP.alpha. andRPTP.epsilon., specifically regulate the insulin receptor signallingpathway. Compounds that specifically modulate the activity of thecontrolling RPTP, thereby prolonging or enhancing signal transductionmediated by the insulin receptor can thus be used to treat criticalillness in a patient and/or Critical Illness Polyneuropathy or tomanufacture a medicine to treat critical illness in a patient and/orCritical Illness Polyneuropathy. Such compounds have low toxicity sincethey are specific for the PTPs associated with insulin receptoractivity, and do not significantly affect the activity of other PTPsthat are non-specific.

One object of the present invention is to increase the survival rate ofa critically ill patient and/or a CIPNP patient.

Another object of the present invention is to find a life saving drugfor a critically ill patient and/or a CIPNP patient.

A further object of the present invention is to find a life savingtreatment of critically ill patients and/or a CIPNP patient.

A still further object of the present invention is to reduce the time acritically ill patient and/or a CIPNP patient, stays within an ICU.

Another object of the present invention is to shorten the time acritically ill patient and/or a CIPNP patient, stays at the hospital.

Another object of the present invention is to suppress states of CIPNP.

Another object of the present invention is to prevent and/or treatCIPNP.

Another object of the present invention is to prevent and/or treatsepsis and/or its mediators in a critically ill patient and/or in CIPNP.

Another object of the present invention is to find a medicament with anapplication targeted at patients at risk for suffering from CIPNP, forexample when in an ICU. Another object of the present invention is tofind a medicament which can be used for prevention and/or treatment acritically ill patient and/or CIPNP.

Another object of the present invention is to treat a critically illpatient and/or a CIPNP patient, so that he is no longer in need of vitalorgan system support.

Another object of the present invention is to treat a critically illpatient and/or a CIPNP patient, so that it is considered sufficient forhim to receive at least about two third of the caloric need through thenormal enteral route.

Another object of the present invention is to reduce the risk orlikelihood from multiple organ failure in a critically ill patientand/or a CIPNP patient.

Another object of the present invention is to reduce the risk orlikelihood from multiple organ failure with a proven septic focus onpost-mortem examination in a critically ill patient and/or a CIPNPpatient.

Another object of the present invention is to reduce mortality, forexample, in-hospital mortality, in a critically ill patient and/or in aCIPNP patient.

Another object of the present invention is to reduce morbidity, forexample, in-hospital morbidity, in a critically ill patient and/or in aCIPNP patient.

Another object of the present invention is to reduce the use ofmechanical ventilatory support to a critically ill patient and/or to aCIPNP patient.

Another object of the present invention is to reduce the likelihood ofrenal replacement therapy and/or renal failure in a critically illpatient and/or a CIPNP patient.

Another object of the present invention is to reduce the likelihood ofdisturbed kidney function parameters on a critically ill patient and/orin a CIPNP patient.

Another object of the present invention is to reduce the likelihood ofhyperbilirubinemia in a critically ill patient and/or in a CIPNPpatient.

Another object of the present invention is to reduce the likelihood forblood stream infections in a critically ill patient and/or in a CIPNPpatient.

Another object of the present invention is to reduce the likelihood ofdisturbance in markers of inflammations and/or inflammatory responses ina critically ill patient, and/or in a CIPNP patient.

Another object of the present invention is to reduce the use ofantibiotics in a critically ill patient and/or in a CIPNP patient.

Another object of the present invention is to reduce the likelihood of acritically ill patient and/or in a CIPNP patient having repetitivepositive EMGs.

Another object of the present invention is to reduce the amount of redcell transfusion to a critically ill patient and/or to a CIPNP patient.

Another object of the present invention is to prevent or reduce theamount of ultimately futile intensive care to a critically ill patientand/or to a CIPNP patient.

Another object of the present invention is to protect a critically illpatient and/or in a CIPNP patient from cholestasis.

Another object of the present invention is to reduce the need forinvasive treatment in a critically ill patient and/or in a CIPNPpatient.

Another object of the present invention is to reduce the stress inducedhyperglycaemia in a critically ill patient and/or in a CIPNP patient.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1: ICU deaths in different strata of first 24 h-APACHE II and TISSscores. APACHE denotes Acute Physiology and Chronic Health Evaluation.TISS denotes Therapeutic Intervention Scoring System. Filled barsrepresent deaths in the RIS group and hatched bars the deaths in the IISgroup.

FIG. 2: Kaplan-Meier cumulative survival plot for in-hospital survival.The large figure displays results from all patients (P=0.01); the smallfigure displays long-stay (≧5 days) ICU patients only (P=0.018). Boldlines represent the IIS group and thin lines the RIS group. Patientsdischarged from the hospital were considered survivors. P-values wereobtained by logrank (Mantel-Cox) significance testing.

DETAILED DESCRIPTION OF THE INVENTION Definitions

The term “systemic inflammatory response syndrome (SIRS)”, as usedherein refers to the uncontrolled disease process which ensues aninitial insult and which gives rise to a multisystem disturbancesecondary to inflammatory mediators released during shock.

The term “sepsis”, as used herein refers to “SIRS”, as described above,which is particularly caused by an infectious insult leading to theinitial shock phase.

The term “mediators of sepsis”, as used herein refers to factorsreleased by inflammatory cells, such as TNFs, interleukins, bradykininsetc.

The term “insulin receptor type tyrosine kinase”, as used herein refersto a post-receptor signal transduction pathway involved in the insulinsignaling.

The term “endoneural edema”, as used herein refers to swelling of theneuronal cells.

The term “phrenic nerves”, as used herein refers to the left and rightnervus phrenicus, innervating the diaphragm.

The term “blood glucose regulator”, as used herein refers to anycompound which is able to regulate the blood glucose level. Examples ofblood glucose regulators are insulin, active insulin derivatives,insulin analogues, compounds that stimulate signal transduction mediatedby an insulin receptor type tyrosine kinase in a cell, certainprotein-tyrosine phosphatases (PTP's), other type II antidiabetica, andother biologically active substances having insulin releasing action.

The term “insulin”, as used herein refers to insulin from any speciessuch as porcine insulin, bovine insulin, and human insulin and saltsthereof such as zinc salts, and protamin salts.

The term “active derivatives of insulin”, as used herein are what askilled art worker generally considers derivatives, vide generaltextbooks, for example, insulin having a substituent not present in theparent insulin molecule.

The term “insulin analogues”, as used herein refers to insulin whereinone or more of the amino acid residues have been exchanged with anotheramino acid residue and/or from which one or more amino acid residue hasbeen deleted and/or from which one or more amino acid residue has beenadded with the proviso that said insulin analogue has a sufficientinsulin activity. Using results from the so-called free fat cell assay,any skilled art worker, for example, a physician, knows when and whichdosages to administer of the insulin analogue. Examples of insulinanalogues are described in the following patents and equivalentsthereto: U.S. Pat. No. 5,618,913, EP 254,516, EP 280,534, U.S. Pat. No.5,750,497, and U.S. Pat. No. 6,011,007. Examples of specific insulinanalogues are insulin aspart (i.e., Asp^(B28) human insulin), insulinlispro (i.e., Lys^(B28), Pro^(B29) human insulin), and insulin glagin(i.e., Gly^(A21), Arg^(B31), Arg^(B32) human insulin).

Also compounds which can be considered being both an insulin derivativeand an insulin analogue can be used to practice the present invention.Examples of such compounds are described in the following patents andequivalents thereto: U.S. Pat. No. 5,750,497, and U.S. Pat. No.6,011,007. An example of a specific insulin analogues and derivatives isinsulin detenir (i.e., des-Thr^(B30) human insulin γLys^(B29)tetradecanoyl).

The term “non-diabetic patient”, as used herein refers to a patient whohas not been diagnosed as having diabetes.

In its broadest sense, the term a “critically ill patient” (hereindesignated CIP), as used herein refers to a patient who has sustained orare at risk of sustaining acutely life-threatening single or multipleorgan system failure due to disease or injury, a patient who is beingoperated and where complications supervene, and a patient who has beenoperated in a vital organ within the last week or has been subject tomajor surgery within the last week. In a more restricted sense, the terma “critically ill patient”, as used herein refers to a patient who hassustained or are at risk of sustaining acutely life-threatening singleor multiple organ system failure due to disease or injury, or a patientwho is being operated and where complications supervene. In an even morerestricted sense, the term a “critically ill patient”, as used hereinrefers to a patient who has sustained or are at risk of sustainingacutely life-threatening single or multiple organ system failure due todisease or injury. Similarly, these definitions apply to similarexpressions such as “critical illness in a patient” and a “patient iscritically ill”.

The term “Intensive Care Unit” (herein designated ICU), as used hereinrefers to the part of a hospital where critically ill patients aretreated. Of course, this might vary from country to country and evenfrom hospital to hospital and said part of the hospital may notnecessary, officially, bear the name “Intensive Care Unit” or atranslation or derivation thereof. Of course, the term “Intensive CareUnit” also covers a nursing home, a clinic, for example, a privateclinic, or the like if the same or similar activities are performedthere.

Treatment Methods of the Invention

Usually and preferably, the treatment of a critical ill patentnecessitates prolonged minute-to-minute therapy and/or observation,usually and preferably in an intensive care unit (ICU) or a specialhospital unit, for example, a post operative ward or the like which iscapable of providing a high level of intensive therapy in terms ofquality and immediacy.

Examples of a critically ill patient is a patient in need of cardiacsurgery, cerebral surgery, thoracic surgery, abdominal surgery, vascularsurgery, or transplantation, or a patient suffering from neurologicaldiseases, cerebral trauma, respiratory insufficiency, abdominalperitonitis, multiple trauma, severe burns, or CIPNP.

The glucose metabolism of the a clinical ill patient may be controlledby clamping the blood glucose level within the ranges mentioned inconnection with the present invention. Any skilled art worker, forexample, a physician, knows how to do this, for example using insulin oranother blood glucose regulator. Any skilled art worker is able to findthe pharmaceutically effective amount of the blood glucose regulatorused and to determine how often it is to be administered. Specificreference can be made to brochures concerning regulation of the bloodglucose level, available from Novo Nordisk A/S, and a huge number ofother publications.

Conveniently, the blood glucose level is kept within the rangesmentioned in connection with the present invention for as long a periodof time as the patient is critically ill. Hence, as a general rule, theblood glucose level is kept within the ranges mentioned in connectionwith the present invention as long as the patient is critically ill.Consequently, the blood glucose level is usually kept within the rangesmentioned in connection with the present invention for a period of timeof more than about 8 hours, preferably more than about 24 hours, evenmore preferred more than about 2 days, especially more than about 4days, and even more than about 7 days. In certain cases, it may even bepreferred that the blood glucose level is kept within the rangesmentioned in connection with the present invention after the patient(previously) considered as being critically ill has been transferredfrom the Intensive Care Unit to another part of the hospital or evenafter said patient has left the hospital.

A critical ill patient, optionally entering an ICU, may be fedcontinuously, on admission with mainly intravenous glucose (for example,about 200 g to about 300 g per 24 hours) and from the next day onwardwith a standardised feeding schedule aiming for a caloric content up tobetween about 10 and about 40, preferably between about 20 and about 30,non-protein Calories/kg/24 hours and a balanced composition (forexample, between about 0.05 and about 0.4, preferably between about 0.13and about 0.26, g nitrogen/kg/24 hours and between about 20% and about40% of non-protein Calories as lipids) of either total parenteral,combined parenteral/enteral or full enteral feeding, the latter modeattempted as early as possible. Other comcomitant ICU therapy can beleft to the discretion of attending physicians.

Alternatively, the following procedure can be used or it is possible touse a combination or variant of these procedures, as the physicianconsiders advantageous for the patient:

A critical ill patient may be fed, on the admission day, using, forexample, a 20% glucose infusion and from day 2 onward by using astandardised feeding schedule consisting of normal caloric intake (forexample, about 25-35 Calories/kgBW/24 h) and balanced composition (forexample, about 20%-40% of the non-protein Calories as lipids and about1-2 g/kgBW/24 h protein) of either total parenteral, combinedparenteral/enteral or full enteral feeding, the route of administrationof feeding depending on assessment of feasibility of early enteralfeeding by the attending physician. All other treatments, includingfeeding regimens, were according to standing orders currently appliedwithin the ICU.

The present invention also relates to advertising media and material andinformation media and material containing or giving information aboutthe novel utility, indication, and action of the blood glucoseregulators according to the present invention. Examples of advertisingmedia and material and information media and material a brochure,packaging material which is used for the customer package such as theouter box, the inner box, or a blisterpack, any printed material/leafletsupplied with the drug such as a package insert, a patient leaflet, orpatient information, a label, a web site, a movie, an advertising movie,a video, and the like. Any skilled art worker knows how to manufacturethe above advertising media and material and information media andmaterial. An example of a brochure according to the present invention isa brochure in which it is stated (or suggested) that insulin can be usedto treat CIPNP patients, for example in a ICU.

An advertisement according to the present invention could have thefollowing text:

Furthermore, the present invention relates to a method of selling ablood glucose regulator by giving information about their novel utility,novel activity and/or novel pharmaceutical indications described herein.One method of selling a blood glucose regulator could be by telling aperson, for example, a physician, that insulin can be used to treatCIPNP patients, for example in a ICU. Alternatively, a method of sellinga blood glucose regulator could be by distributing the above advertisingand information media are brochures such as packaging material which isused for the customer package, any printed material/leaflet suppliedwith the drug, or patient information, labels, web sites, movies,advertising movies, videos, and the like. Another method of selling ablood glucose regulator which is covered by the present claims is tosupport a speaker giving information about the novel utility,indication, and action of the blood glucose regulators according to thepresent invention or to support an author writing an article givinginformation about the novel utility, indication, and action of the bloodglucose regulators according to the present invention. Other variationshereof will be obvious for the skilled art worker, for exampledistributing an advertisement as the above.

According to one embodiment, the present invention relates to a use of ablood glucose regulator for the manufacture of a life saving drug totreat or cure a critically ill patient and/or a CIPNP-patient and/or apotential CIPNP-patient.

According to another embodiment, the present invention relates to a useof a blood glucose regulator for the manufacture of a medicament totreat or cure a critically ill patient and/or a CIPNP-patient and/or apotential CIPNP-patient.

According to a further embodiment, the present invention relates to ause of a blood glucose regulator for the manufacture of a medicament toprevent than a patient becomes critical ill or develops CIPNP.

According to a further embodiment, the present invention relates to ause of a blood glucose regulator for the manufacture of a medicament toincreasing the survival rate of a critically ill patient and/or aCIPNP-patient and/or a potential CIPNP-patient.

According to a further embodiment, the present invention relates to ause of a blood glucose regulator for the manufacture of a medicament toreducing the time a critically ill patient and/or a CIPNP-patient and/ora potential CIPNP-patient stays within a hospital, for example stayswithin an ICU.

According to a further embodiment, the present invention relates to ause of a blood glucose regulator for the manufacture of a medicament toprevent, treat or cure SIRS, especially in a critically ill patientand/or a CIPNP-patient and/or a potential CIPNP-patient.

According to a further embodiment, the present invention relates to ause of a blood glucose regulator for the manufacture of a medicament toprevent, treat or cure sepsis and/or its mediators, especially in acritically ill patient and/or a CIPNP-patient and/or a potentialCIPNP-patient.

According to a further embodiment, the present invention relates to ause of a blood glucose regulator for the manufacture of a medicament toreduce mortality, hospitality stay, bacteraemia, need for dialysis andneed for ventilatory support in a critically ill patient and/or aCIPNP-patient and/or a potential CIPNP-patient.

According to a further embodiment, the present invention relates to ause of a blood glucose regulator for the manufacture of a medicament totreat a critically ill patient and/or a CIPNP-patient and/or a potentialCIPNP-patient so that he is no longer in need of vital organ systemsupport or to treat a critically ill patient and/or a CIPNP-patient orand/a potential CIPNP-patient so that it is considered sufficient forhim to receive at least about two third of the caloric need through thenormal enteral route to reduce the risk or likelihood from multipleorgan failure, to reduce the risk or likelihood from multiple organfailure with a proven septic focus on post-mortem examination, to reducemortality, for example, in-hospital mortality, to reduce the use ofmechanical ventilatory support, to reduce the likelihood of renalreplacement therapy and/or renal failure, to reduce the likelihood ofdisturbed kidney function parameters, to reduce the likelihood ofhyperbilirubinemia, to reduce the likelihood for blood streaminfections, to reduce the likelihood of disturbance in markers ofinflammations and/or inflammatory responses, to reduce the use ofantibiotics, to reduce the amount of red cell transfusion, or to reducethe stress induced hyperglycaemia of, in, or to a critically ill patientand/or in a CIPNP-patient or and/a potential CIPNP-patient or to reducethe likelihood of a critically ill patient and/or in a CIPNP-patientand/or a potential CIPNP-patient having repetitive positive EMGs or toprevent or reduce the amount of ultimately futile intensive care to acritically ill patient and/or to a CIPNP-patient or and/a potentialCIPNP-patient or to protect a critically ill patient and/or in aCIPNP-patient or and/a potential CIPNP-patient from cholestasis or toreduce the need for invasive treatment in a critically ill patientand/or in a CIPNP-patient or and/a potential CIPNP-patient or anycondition of insulin resistance leading to hyperinsulinimea incombination with hyperglycaemia in a critically ill patient and/or in aCIPNP-patient or and/a potential CIPNP-patient.

According to a further embodiment, the present invention relates to thenovel uses described herein, wherein the blood glucose regulator isinsulin, active insulin derivatives, insulin analogues, compounds thatstimulate signal transduction mediated by an insulin receptor typetyrosine kinase in a cell, certain protein-tyrosine phosphatases(PTP's), other type II antidiabetica, and other biologically activesubstances having insulin releasing action.

According to a further embodiment, the present invention relates to thenovel use described herein, wherein the blood glucose regulator is ablood glucose regulator which is not to be administered orally.

According to a further embodiment, the present invention relates to thenovel uses described herein, wherein the blood glucose regulator is usedin such a way that the blood glucose level is kept within a range wherethe lower limit is about 60, about 70 or about 80 mg/dL and the upperlimit is about 110, about 120 or about 130 mg/dL, preferably kept in arange from about 80 to about 110 mg/dL).

According to a further embodiment, the present invention relates to thenovel uses described herein, wherein the blood glucose regulator is usedin such a way that the blood glucose level is kept within the range fromabout 60 to about 130, preferably, from about 70 to about 120, morepreferred, from about 80 to about 110 mg/dL.

According to a further embodiment, the present invention relates to thenovel uses described herein, wherein the blood glucose level is keptwithin the ranges mentioned above for a period of time of more thanabout 8 hours, preferably more than about 24 hours, even more preferredmore than about 2 days, especially more than about 4 days, and even morethan about 7 days.

According to a further embodiment, the present invention relates to thenovel uses described herein, wherein the patient to be treated is amammal, preferably a human (being).

According to a further embodiment, the present invention relates to thenovel uses described herein, wherein the patient is a non-diabeticpatient.

According to a further embodiment, the present invention relates to thenovel uses described herein, wherein the patient is a patient in need ofcardiac surgery, cerebral surgery, thoracic surgery, abdominal surgery,vascular surgery, or transplantation, or a patient suffering fromneurological diseases, cerebral trauma, respiratory insufficiency,abdominal peritonitis, multiple trauma, severe burns, or CIPNP.

According to a further embodiment, the present invention relates to anovel method for the treatment, curing or prevention as describedherein, wherein the patient to be treated receives an effective amountof the compound mentioned above and as stated above.

According to a further embodiment, the present invention relates tonovel advertising media and material and information media and materialhaving or giving information about the indications and utilities of ablood glucose regulator described herein and in the way described above.

According to a further embodiment, the present invention relates to anovel method of selling a blood glucose regulator by giving informationof about the indications and utilities of said blood glucose regulatordescribed herein and in the way described herein.

A further, specific embodiment of the present invention relates to thenovel use of a pharmaceutically effective composition for use in thetherapeutic treatment of a mammal having Critical IllnessPolyneuropathy, comprising a pharmaceutically effective amount of acompound which is selected from a group of compounds comprising insulin,its active derivatives and the physiologically tolerated salts of theseinsulin derivatives or of a group of biologically active sub-stanceshaving insulin releasing action or of a group of compounds thatstimulate signal transduction mediated by an insulin receptor typetyrosine kinase in a cell.

Another specific embodiment of the present invention relates to thenovel use of a pharmaceutically effective composition for use in theprophylactic treatment of a mammal having Critical IllnessPolyneuropathy, comprising a pharmaceutically effective amount of acompound which is selected from a group of compounds comprising insulin,its active derivatives and the physiologically tolerated salts of theseinsulin derivatives or of the group of biologically active substanceshaving insulin releasing action or of the group of compounds thatstimulate signal transduction mediated by an insulin receptor typetyrosine kinase in a cell.

A further embodiment of the present invention relates to the novel useof compounds of the group of compounds comprising insulin, its activederivatives and the physiologically tolerated salts of these insulinderivatives or of a group of biologically active substances havinginsulin releasing action or of a group of compounds that stimulatesignal transduction mediated by an insulin receptor type tyrosine kinasein a cell for the manufacturing of a medicament for the treatment orprevention of Critical Illness Polyneuropathy.

A still further embodiment of the present invention relates to a novelmethod for the treatment of Critical Illness Polyneuropathy in mammals,wherein said critical ill individual (or patient) receives an effectiveamount of a compound to keep the blood glucose levels between 80 and 110mg/dL (4.6-6.1 mmol/L), i.e., in reality or in practice between about 80and about 110 mg/dL (i.e., between about 4.6 and about 6.1 mmol/L).

Another specific embodiment of the present invention relates to thenovel method described in the previous paragraph (wherein CIPNP istreated with a compound to keep the blood glucose levels between 80 and110 mg/dL) whereby said compound is selected from a group of compoundscomprising insulin, its active derivatives and the physiologicallytolerated salts of these insulin derivatives or of a group ofbiologically active substances having insulin releasing action or of agroup of compounds that stimulate signal transduction mediated by aninsulin receptor type tyrosine kinase in a cell.

In a further preferred embodiment of the present invention, the criticalill patient is a patient in need of cardiac surgery.

In another preferred embodiment of the present invention, the criticalill patient is a patient in need of cerebral surgery.

In a further preferred embodiment of the present invention, the criticalill patient is a patient in need of thoracic surgery.

In a further preferred embodiment of the present invention, the criticalill patient is a patient in need of abdominal surgery.

In a further preferred embodiment of the present invention, the criticalill patient is a patient in need of vascular surgery.

In a further preferred embodiment of the present invention, the criticalill patient is a patient in need of transplantation.

In a further preferred embodiment of the present invention, the criticalill patient is a patient suffering from neurological diseases.

In a further preferred embodiment of the present invention, the criticalill patient is a patient suffering from cerebral trauma.

In a further preferred embodiment of the present invention, the criticalill patient is a patient suffering from respiratory insufficiency.

In a further preferred embodiment of the present invention, the criticalill patient is a patient suffering from abdominal peritonitis.

In a further preferred embodiment of the present invention, the criticalill patient is a patient suffering from multiple trauma.

In a further preferred embodiment of the present invention, the criticalill patient is a patient suffering from severe burns.

In a further preferred embodiment of the present invention, the criticalill patient is a patient suffering from CIPNP.

In a further preferred embodiment of the present invention, the criticalill patient is a patient being mechanically ventilated.

EXAMPLES

The terminology used herein is for the purpose of describing particularembodiments only, and is not intended to limit the scope of the presentinvention which will be limited only by the appending claims. Thisinvention is not limited to the particular methodology, protocols,delivery forms and reagents described as these may vary.

Example 1 Material and Methods

In a prospective clinical study, we tested the hypothesis that theincidence of CIPNP can be reduced by more strict metabolic usingintensive insulin treatment from admission onward.

Between 2 Feb. and 25 Apr. 2000, 400 patients were included in thestudy. They had been randomly allocated to one of two insulin (ActrapidHM NovoLet of Novo Nordisk) treatment schedules:

-   (1) insulin infusion started at a dose of 1 U/h only when blood    glucose is >230 mg/dL (13 mmol/L) and titrated up (2 to 4 hourly    controls of blood glucose levels) with increments of 0.5 to 1 U/h to    keep blood glucose below this level [180-200 mg/dL (10.3-11.2    mmol/L)]. When blood glucose levels reach 180 mg/dL, insulin    infusion is stopped.-   (2) insulin infusion started when blood glucose is >120 mg/dL (6.8    mmol/L) at a dose of 2 U/h and titrated up (2 to 4 hourly controls    of blood glucose levels) with increments adequate to keep blood    glucose levels normal and thus below this level [80-110 mg/dL    (4.6-6.1 mmol/L)]. Maximal hourly insulin dose is set at 60 Upper    hour. When blood glucose levels reach 80 mg/dL, insulin infusion is    tapered and eventually stopped until normal levels are again    reached. During interruption of enteral tube feeding for    determination of residual stomach content, insulin infusion is    reduced proportionately to the reduction of caloric intake.-   (3) Concomitantly, patients were fed, on the admission day using a    20% glucose infusion and from day 2 onward by using a standardised    feeding schedule consisting of normal caloric intake (25-35    Calories/kgBW/24 h) and balanced composition (20%-40% of the    non-protein Calories as lipids & 1-2 g/kgBW/24 h protein) of either    total parenteral, combined parenteral/enteral or full enteral    feeding, the route of administration of feeding depending on    assessment of feasibility of early enteral feeding by the attending    physician. All other treatments, including feeding regimens, were    according to standing orders currently applied within the ICU.    Exclusion criteria were age <18y, pregnancy and not being intubated    at admission.

When patients were still treated in the ICU after 7 days, a weekly EMGexamination was performed to screen for the presence of CIPNP. The EMGswere always interpreted by the same expert in electrophysiology. Inorder to accurately assess ICU stay, which is often determined by otherfactors than the patient's condition—e.g. bed availability on thewards—“end of ICU stay” was defined as the day on which the attendingphysician considers the patient to be “ready for discharge”.

Results

83 patients ended up being treated on the ICU for at least one week andwere screened by EMG for the presence of CIPNP. In the group randomisedinto the “intensive insulin schedule”, 38 patients stayed for more than7 days and in the group randomised into the “restrictive insulinschedule”, 45 patients stayed more than 7 days. Fifteen out of 38long-stay ICU patients in the intensive insulin group (or 39% of thelong stayers) revealed a positive EMG for CIPNP at any time during theICU stay versus 30 out of 45 in the restrictive insulin group (or 67%)(P=0.01 with Chi-square).

In the intensive insulin group, the mean±SD number of positive EMGs forCIPNP per patient was 0.9±1.8 (median of zero) versus 1.8±2.1 (medianof 1) in the restrictive insulin group (P=0.015 with Mann-Whitney Utest).

Long-stay patients in the intensive insulin group had a CIPNP-free timeon the ICU of 2.1±1.8 weeks versus 1.1±1.2 weeks in the restrictiveinsulin group (P=0.004 with unpaired Student's t-test).

ICU-mortality was not detectably different between the two treatmentgroups (P=0.4).

Conclusions

This study revealed that strict metabolic control with intensive insulintreatment and clamping of blood glucose levels within normal limitssignificantly reduces the incidence of CIPNP and lengthens the time freeof CIPNP in patients that do develop this problem. This is the firststudy to point to a preventive strategy for this frequently occurringand important problem in ICU patients. Since the presence of EMG-provenCIPNP has been shown to extend the need for ICU support and to prolongthe time required for rehabilitation, this treatment will lead to areduction in need for ICU support and to a shorter time forrehabilitation, which could reflect a major reduction in costs.

Example 2 A Prospective, Randomized, Controlled Study was Performed

All mechanically ventilated, adult patients admitted to the intensivecare unit (ICU) were eligible for inclusion. Only 5 patientsparticipating in another trial and 9 who were moribund or DNR coded atICU admission were excluded. At admission, patients were randomized toeither strict normalization of glycemia (4.5-6.1 mmol/L) withcontinuously infused insulin during intensive care, the ‘intensiveinsulin schedule’ (IIS), or the currently used ‘restrictive insulinschedule’ (RIS), with insulin started when blood glucose exceeds 12mmol/L in which case glycemia is clamped to 10-12 mmol/L. An interimsafety analysis revealed a difference in mortality, and the study wasended for ethical reasons.

Results

A total of 1548 patients were included, 765 in the IIS group, 783 in theRIS group, well matched at inclusion. IIS reduced ICU mortality by 43%(P=0.005) [63 deaths in the RIS group versus 35 in the IIS group; deathodds ratio for IIS, corrected for all baseline univariate predictors ofICU death, was 0.52 (0.33-0.82), P=0.004] and hospital mortality by 34%(P=0.01). Mortality reduction occurred exclusively in long-stay ICUpatients and was due to prevention of death from multiple organ failurewith sepsis. IIS also reduced the incidence of blood stream infections,renal failure, anemia and critical illness polyneuropathy as well as theneed for dialysis or hemofiltration, red cell transfusion, prolongedmechanical ventilatory support and intensive care.

Conclusion

The data suggest that disturbances in glucose metabolism during criticalillness are not “adaptive and beneficial” since strict metabolic controlwith exogenous insulin substantially reduces morbidity and mortality.

More detailed, the study was as follows:

Study Population

All mechanically ventilated, adult (age>18y) patients admitted to our56-bed, mainly surgical, ICU from Feb. 2, 2000 onward were consideredeligible for inclusion. Only 5 patients taking part in other outcometrials and 9 who were moribund or “do not resuscitate”—coded at ICUadmission were excluded. Informed consent was obtained from the closestfamily member. The study protocol was approved by the InstitutionalReview Board of the Catholic University of Leuven School of Medicine.

Study design and treatment protocols: t ICU admission, patients wererandomized to either strict control of glycemia below 6.1 mmol/L (110mg/dL) with continuously infused insulin, the ‘intensive insulinschedule’ (IIS), or the currently used ‘restrictive insulin schedule’(RIS), with insulin started when blood glucose exceeds 12 mmol/L (215mg/dL). In the RIS group, intravenous insulin drip, consisting of 50 IUinsulin (Actrapid HM®, Novo Nordisk, Denmark) in a 50 mL NaCl 0.9%containing PERFUSOR® syringe driven by a Perfusor FM® pump (B. Braun,Melsungen, Germany), was initiated at 1 IU/h. By 2-4 hourly measurementsof whole blood glucose levels in undiluted arterial blood samples usingthe ABL700 analyser (Radiometer Medical A/S, Copenhagen, Denmark),insulin dose was adjusted to clamp glycemia between 10-12 mmol/L.

In the IIS group, insulin drip was started at 2 IU/h when blood glucoseexceeded 6.1 mmol/L. By 2-4 hourly measurements—and in case of difficultcontrol by hourly measurements—of blood glucose levels, insulin dose wasadjusted to clamp glycemia between 4.5-6.1 mmol/L. Maximal dose ofinsulin was arbitrarily set at 50 U/h. At ICU discharge, a restrictiveinsulin schedule was adopted (glycemia ≦12 mmol/L) to avoid hypoglycemiain the less well controlled setting of a regular ward.

Consecutive patients were randomly assigned to one of these twotreatment groups using blinded envelopes, stratified according to typeof critical illness diagnosed on admission [(a) neurological disease,cerebral trauma or surgery; (b) cardiac surgery; (c) thoracic surgeryand/or respiratory insufficiency; (d) abdominal surgery/peritonitis; (e)vascular surgery; (f) multiple trauma or severe burns: (g) organtransplantation; (h) others, mainly extensive oncological procedures]and balanced with the use of permuted blocks of ten.

All patients were fed continuously, on admission with mainly intravenousglucose (200-300 g/24 h) and from the next day onward with astandardised feeding schedule aiming for a caloric content up to 20-30non-protein Calories/kg/24 h and a balanced composition (0.13-0.26 gnitrogen/kg/24 h and 20%-40% of non-protein Calories as lipids) ofeither total parenteral, combined parenteral/enteral or full enteralfeeding, the latter mode attempted as early as possible. Othercomcomitant ICU therapy was left to the discretion of attendingphysicians.

Baseline Assessment and Data Collection

At baseline, demographic, diagnostic and therapeutic information as wellas information necessary to determine severity of illness andutilization of ICU resources were obtained from each patient (Table 1).These included APACHE-II (Acute Physiology and Chronic HealthEvaluation) score with higher values indicating more severe illness (seeKnaus) and simplified Therapeutic Intervention Scoring System (TISS-28)with higher values indicating a higher number of therapeuticinterventions (see Reis Miranda & Keene). APACHE II and TISS scores werecalculated daily from ICU admission to discharge or death.

The ‘on-admission’ APACHE II score was calculated from data gatheredduring 24 h after admission to the ICU and omitted values fromstabilization in the emergency department or recovery room prior totransfer. Because of ICU bed shortage, this period outside ICU oftentook more than 24 h which caused a substantial treatment effect and thuslowered APACHE II scores. Moreover, zero points were usually assignedfor the neurological evaluation section (Glasgow Coma Score, with highervalues indicating more impaired consciousness) as the majority ofpatients were sedated upon ICU admission which makes correctconsciousness scoring impossible. This approach is the most consistentand objective but inevitably reduces APACHE II (see Knaus).

A blood sample was taken upon ICU admission and daily at 06:00 h untildischarge from ICU or death. On-admission and daily morning, whole bloodglucose level as well as daily maximal and minimal glycemia wereanalysed. Analyses on the 06:00 h sample also included clinicalchemistry, hematology and markers of inflammation.

Blood cultures were taken whenever continously monitored central bodytemperature acutely rose above 38.5° C. Results from all blood cultureswere interpreted by the same blinded investigator. An episode ofbacteremia, fungemia or mycobacteremia was defined by the first positiveblood culture in a series. To identify a blood stream infection withcoagulase-negative staphylocci, identical strains (compared byantibiogram) of microorganisms in two or more positive blood cultureswere required (see Weinstein 1997 and Weinstein 1998).

In patients treated in ICU for more than one week, a weeklyelectromyography (EMG) was performed to screen for Critical IllnessPolyneuropathy. EMGs were interpreted by the same electrophysiologistwho was blinded for randomization.

In case of ICU death, a post-mortem examination was performed to confirmthe presumed cause of death. The pathologists were also blinded for theinsulin treatment schedule.

Outcome Measures:

The primary outcome measure was death from all causes during intensivecare. Secondary outcome measures were in-hospital mortality, incidenceof prolonged intensive care dependency and need for ICU re-admission,need for vital organ system support comprising mechanical ventilatorysupport, renal replacement therapy (continuous or intermittenthemofiltration or dialysis), inotropic or vasopressor support, incidenceof critical illness polyneuropathy, the degree of inflammation,incidence of blood stream infections and use of antibiotics, transfusionrequirements and incidence of hyperbilirubinemia. Furthermore, use ofintensive care resources was analysed by cumulative TISS scores. Inorder to accurately and objectively assess duration of ICU stay, whichis often influenced by non-patient related factors such as bedavailability on regular wards, patients were defined ‘dischargable fromICU’ when they were no longer in need of vital organ system support andreceived at least ⅔rd of the caloric need through the normal enteralroute or earlier when actually sent to a ward.

Statistical Analysis:

We hypothesized to detect a difference in mortality selectively inlong-stay (>5 days) critically ill patients. Since prolonged ICU stay isnot predictable at ICU admission, and since we aimed at treatment fromadmission onward, we chose to include all mechanically ventilatedpatients admitted to the ICU, without selection. We estimated thatinclusion of 2500 admissions would be needed to rule out an absolutedifference in mortality of ±5% in the long-stay cohort which wouldtranslate in an absolute risk reduction of ±2% for overall ICU mortality(2-sided alfa level of <0.05). Three-monthly interim analyses of overallICU mortality were performed with stopping bounderies (with a 2-sidedalfa-level of <0.01) designed to allow early study termination if one ofthe intervention groups was found to be clearly inferior. Interimanalysis after one year of study revealed a significantly higher numberof deaths in the RIS group, after which the study was ended for ethicalreasons. All analyses were done on intention to treat basis.

Baseline and outcome variables were compared using Student's t-test,Chi-square test and Mann-Whitney-U test, as appropriate. Death oddsratios were calculated using multivariate logistic regression analysis.The effect on time of in-hospital death was assessed by Kaplan-Meieranalysis and logrank (Mantel-Cox) significance testing. Patientsdischarged from the hospital were considered as survivors. Data arepresented as percentages, means±SD or medians (25^(th)-75^(th)percentile) unless indicated otherwise.

Results Study Population:

The study involved 1548 patients, 783 in the RIS group and 765 in theIIS group, well matched at randomization (Table 1) although IIS patientstended to be slightly older and more obese compared with RIS patients.

A history of diabetes was present in 13.2% of patients, 4.6% treatedwith subcutaneous insulin injections, 8.6% receiving oral anti-diabetictreatment. On ICU admission, 74.6% of patients revealed glycemia higherthan normal when compared with overnight fasted reference values (≧6.1mmol/L) and 56% had a blood glucose level higher than the fasteddiabetes threshold (≧7 mmol/L). Only 11.7%, however, revealed anon-admission glycemia in the non-fasting diabetes range (≧11 mmol/L). Anon-fasting “diabetic” glycemia on ICU admission did not correlate wellwith having a history of diabetes, as only 19.6% of the known diabeticsrevealed a blood glucose level on ICU admission ≧11 mmol/L. The twostudy groups were comparable for diabetes diagnosed before ICU admissionand for incidence of on-admission hyperglycemia (Table 1).

Glycemia Control:

Mean and maximal amount of non-protein Calories per patient (notincluding the first and last day of ICU stay) was 19±7 kCal/kg/24 h and24±10 kCal/kg/24 h, respectively. Mean and maximal amount of dietarynitrogen was 0.14±0.06 gN/kg/24 h and 0.19±0.08 gN/kg/24 h,respectively. Daily amounts and composition of the feeding regimens werecomparable in the two groups.

In the IIS group, 99% of patients required exogenous insulin, a needwhich persisted for the entire duration of ICU stay (Table 2). Glycemiawas well controlled with mean morning levels of 5.8±1.0 mmol/L. Only0.1% of IIS patients had blood glucose levels that failed to go below6.1 mmol/L within 48 h, 48% never exceeded 6.1 mmol/L after treatmentinitiation and only 17% occasionally peaked over 8.4 mmol/L. Meanmorning glycemia in the RIS group was 8.5±1.8 mmol/L. Only 39% of RISpatients actually received insulin and those revealed a mean morningglycemia of 9.6±1.8 mmol/L in contrast to 7.8±1.4 mmol/L in thenon-insulin requiring RIS patients.

In 39 IIS-treated patients, glycemia transiently fell below 2.3 mmol/Lversus 6 patients in the RIS group. Such an event of hypoglycemia wasalways quickly corrected and never induced serious symptoms such ashemodynamic deterioration or epilepsia.

Mortality Outcome (Tables 3 & 4; FIGS. 1 & 2)

In the IIS group, 35 patients (4.6%) died during intensive care versus63 (8.1%) in the RIS group (P=0.005), a relative risk reduction (RRR) of43% (Table 3). The “numbers needed to treat” (NNT) to save one lifeduring intensive care was 29. The impact on ICU mortality by IIS wasindependent of the first 24 h-APACHE II and TISS scores (FIG. 1). Theintervention effect was also similar in patients after cardiac surgeryand those suffering from other types of critical illness. ICU mortalityamong the RIS patients actually receiving insulin was 12.4% versus 5.2%among those not requiring insulin to keep glycemia below 12 mmol/L(P=0.0003).

Since we hypothesized a difference in mortality among long-stay ICUpatients, we sub-analysed the effect in patients with an ICU stay of ≦5days and in those staying >5 days. First 24 h-APACHE II score ofpatients staying ≦5 days was a median 9 (IQR 6-12) and 75% of them werepatients after cardiac surgery. Median first 24 h-APACHE II in patientsstaying >5 days was 12 (8-15) and 68% were suffering from a non-cardiacsurgery type of critical illness. The number of patients with an ICUstay of >5 days was not statistically different in the IIS (27%) and RIS(31%) groups (P=0.1). Mortality of patients staying ≦5 days was similarin IIS and RIS groups. Hence, the reduction in ICU mortality by IISoccurred selectively in the prolonged critically ill cohort with anabsolute and relative risk reduction of 9.6% and 47%, respectively, andone life saved for every 11 treated long-stay patients.

All on-admission risk factors for ICU mortality were determined usingunivariate analysis. These comprised the first 24 h-APACHE II score,age, a non-cardiac surgery type of critical illness, tertiary referral,history of malignancy, and on-admission blood glucose level ≧11 mmol/L.These factors were subsequently entered into a multivariate logisticregression model together with the randomized insulin schedule (Table4). This revealed that the independent risk factors for mortality werethe first 24 h-APACHE II score, age, a non-cardiac surgery type ofcritical illness, tertiary referral and insulin treatment schedule. Thedeath odds ratio for IIS, corrected for other baseline univariatepredictors of ICU death, was 0.52 (95% confidence intervals 0.33-0.82).Analysis of the causes of death during intensive care revealed that IISparticularly reduced the risk of death from multiple organ failure witha proven septic focus on post-mortem examination (Table 3).

IIS also significantly reduced total in-hospital mortality from 10.8% to7.1% (P=0.01), a relative risk reduction of 34% (Table 3, FIG. 2).Again, this benefit was limited to the prolonged critically ill cohort.

Morbidity Outcome (Table 5)

IIS reduced duration of ICU stay whereas in-hospital stay was notdetectably different between the two study groups. ICU re-admission ratewas 2.1% and similar in both groups. In the IIS group, significantlyless patients required prolonged mechanical ventilatory support andrenal replacement therapy compared with the RIS group, whereas the needfor inotropic or vasopressor support was identical. Independent of renalreplacement therapy, kidney function parameters were more disturbed inthe RIS group. The incidence of hyperbilirubinemia was significantlylower in the IIS group.

There was a 46% reduction in blood stream infections. Moreover, markersof inflammation were less disturbed and prolonged use of antibiotics(>10 days) less often required in the IIS group. The latter was largelyattributable to the effect on bacteremia (75% of bacteremic patientswere treated with antibiotics for >10 days versus 10% of non-bacteremicpatients; P<0.0001). Mortality tended to be lower in bacteremic IISpatients (12.5%) compared with bacteremic RIS patients (29.5%; P=0.067).There was no difference between the two groups in the use of ICU drugsother than insulin or antibiotics.

Patients with an ICU stay of more than 1 week were screened weekly forcritical illness polyneuropathy. Firstly, due to the effect on ICU stay,less IIS patients were screened. Secondly, among the screened patientsin the IIS group, less revealed a positive EMG compared with the RISgroup. Among screened patients, the NNT to prevent critical illnesspolyneuropathy in one patient was 4. Furthermore, critical illnesspolyneuropathy resolved more rapidly in the IIS group, as indicated by alower fraction of patients with repetitive positive EMGs on the weeklyscreenings.

The use of aminoglycosides and glucocorticoids were determinants ofcritical illness polyneuropathy by univariate analysis. However, whenentered into a multivariate logistic regression model together withother univariate predictors, the only independent determinants ofcritical illness polyneuropathy remained restrictive insulin schedule[or of 2.6 (1.6-4.2); P=0.0002], >3 days vasopressor treatment [or of2.5 (1.4-4.2); P=0.001], acquiring a blood stream infection [or of 2.3(1.3-4.1); P=0.006] and receiving renal replacement therapy [or of 1.9(1.0-3.8); P=0.05].

When the risk of critical illness polyneuropathy was evaluated in bothstudy groups as function of the actual mean glycemia per patient, apositive, linear correlation was obtained.

The amount of red cell transfusions in IIS patients was only half thatof RIS patients. This was not due to a more liberal transfusion strategyin RIS patients as indicated by their lower levels of hemoglobin andhematocrit (Table 5).

The cumulative TISS score is an indicator of the number of therapeuticinterventions per patient and per ICU stay (see Reis Miranda). There wasa 20% reduction in median cumulative TISS score selectively in long-staypatients. In view of a comparable TISS score on the last day of study[median of 30 (26-38) in both study groups], this difference reflects a20% reduction in costs per long-stay ICU patient (see Reis Miranda).

Discussion

In this large prospective, randomized, controlled study of intensivecare-dependent critically ill patients, tight glycemic control below 6.1mmol/L with insulin reduced ICU mortality by 43% and in-hospitalmortality by 34%. Strict metabolic control also substantially improvedmorbidity by preventing blood stream infections, renal failure, anemia,critical illness polyneuropathy and need for prolonged support offailing vital organ systems. These striking benefits were independent ofthe type and severity of underlying disease.

The beneficial effects on morbidity can be summarized as reducing therisk of several key problems in intensive care. These include acquiringsevere infections and ensuing inflammatory response, development ofrenal failure, cholestasis, anemia, critical illness polyneuropathy andmuscle weakness. These problems perpetuate the need for intensive carewhich, in view of the high mortality of prolonged critical illness,often becomes futile.

In conclusion, the data suggest that disturbances in glucose metabolismin critically ill patients are not “adaptive and beneficial” sincestrict glycemic control during intensive care substantially reducesmorbidity and mortality.

REFERENCES

-   Knaus: Knaus W A, Draper E A, Wagner D P, Zimmerman J E. APACHE II:    A severity of disease classification system. Crit Care Med. 1985;    13:818-829.-   Reis Miranda Reis Miranda D, de Rijck A, Schaufeli W. Simplifed    Therapeutic Intervention Scoring System: the TISS-28 items—results    from a multicenter study. Crit Care Med. 1996; 24: 64-73.-   Keene: Keene A R, Cukken D J. Therapeutic Intervention Scoring    System: Update 1983. Crit Care Med. 1983; 11: 1-3.-   Weinstein 1997: Weinstein M P, Towns M L, Quartey S M, Mirrett S,    Reimer L G, Parmigiani G, Reller L B. The clinical significance of    positive blood cultures in the 1990s: a prospective comprehensive    evaluation of the microbiology, epidemiology and outcome of    bacteremia and fungemia in adults. Clin Infect Dis. 1997; 24:    584-602.-   Weinstein 1998: Weinstein M P, Mirrett S, Van Pelt L, McKinnon M,    Zimmer B L, Kloos W, Reller L B. Clinical importance of identifying    coagulase-negative staphylocci isolated from blood cultures:    evaluation of microscan rapid and dried overnight gram-positive    panels versus a conventional reference method. J Clin Microbiol.    1998; 36: 2089-2092.

TABLES AND FIGURES

TABLE 1 BASELINE PATIENT CHARACTERISTICS RIS IIS P-value N 783 765 Malegender (% of patients)  71  71 0.9 Age (y) (mean ± SD) 62.2 ± 13.9 63.4± 13.6 0.08 BMI (kg/m{circumflex over ( )}2) (mean ± SD) 25.8 ± 4.7 26.2 ± 4.4  0.1 Diagnostic group (total no. - %) cardiac surgery 493(63%) 477 (62%) 0.8 other types of critical illness 290 (37%) 288 (38%)neurological disease, cerebral trauma or surgery 30 (4%) 33 (4%)thoracic surgery and/or respiratory insufficiency 56 (7%) 66 (9%)abdominal surgery/peritonitis 58 (7%) 45 (6%) vascular surgery 32 (4%)30 (4%) multiple trauma or severe burns 35 (4%) 33 (4%) transplantation44 (6%) 46 (6%) others 35 (5%) 35 (5%) APACHE II score (median & IQR)during the first 24 h 9 (7-13) 9 (7-13) 0.4 during the second 24 h 9(6-13) 9 (6-13) 0.8 First 24 h APACHE II score 9 (total no. - %) 458(51%) 429 (48%) 0.3 TISS score (median & IQR) during the first 24 h 43(36-47) 43 (37-46) 0.7 during the second 24 h 38 (32-44) 38 (31-43) 0.4Tertiary referral (% of patients) 17% 17% 0.7 History of malignancy (%of patients) 15% 16% 0.7 History of diabetes (% of patients) 13% 13% 0.9On admission blood glucose 6.1 mmol/L (% of patients) 76% 73% 0.1 Onadmission blood glucose 11 mmol/L (% of patients) 12% 11% 0.2 APACHEdenotes Acute Physiology and Chronic Health Evaluation. Higher APACHE IIscores reflect more severe critical illness. First 24h-APACHE II scoreswere artificially lowered by treatment effect and by assuming normalconsciousness in sedated patients. TISS denotes Therapeutic InterventionScoring System, with each therapeutic intervention being assigned 1 to 4points. An increasing score represents increasing intensity oftreatment. The sum of points is calculated daily for each patient.P-values were obtained using Student's t-test, Mann-Whitney-U test andChi-square test, when appropriate.

TABLE 2 GLYCEMIA CONTROL RIS IIS (N = 783) (N = 765) P-value Patientsreceiving insulin - total no. (%) 307 (39%) 755 (99%) <0.0001 Mean dailyinsulin dose, when given (IU/d) (median - IQR) 33 (17-56) 71 (48-100)<0.0001 Duration of insulin requirement (% of ICU stay) (median - IQR)67 (40-100) 100 (100-100) <0.0001 Mean 06:00 h blood glucose level(mmol/L) (mean ± SD) 8.5 ± 1.8 5.7 ± 1.0 <0.0001 Mean 06:00 h bloodglucose level when on insulin (mmol/L) (mean ± SD) 9.6 ± 1.8 5.7 ± 1.0<0.0001 P-values were obtained using Student's t-test, Mann-Whitney-Utest and Chi-square test, when appropriate.

TABLE 3 MORTALITY ANALYSIS RIS IIS Outcome measure (N = 783) (N = 765)RRR (%) NNT P-value ICU deaths - total no. (%) 63 (8.1%) 35 (4.6%) 43 290.005 Death Odds Ratio corrected for other baseline risk factors (95%CI) 0.52 (0.33-0.82) 0.004 ICU deaths in acute vs. prolonged criticalillness ICU deaths among patients staying {hacek over (S)} 5 days -total no. (%) 14 (2.6%) 13 (2.3%) = 0.8 ICU deaths among patientsstaying >5 days - total no. (%) 49 (20.2%) 22 (10.6%) 47 11 0.005 ICUdeaths per on-admission diagnostic group Cardiac surgery - total no. (%)25 (5%) 10 (2%) Other types of critical illness - total no. (%) 38(13.1%) 25 (8.7%) Neurological disease, cerebral trauma or surgery -total no. (%) 7 (23.3%) 6 (18.1%) Thoracic surgery and/or respiratoryinsufficiency - total no. (%) 10 (17.9%) 5 (7.6%) Abdominalsurgery/peritonitis - total no. (%) 9 (15.5%) 6 (13.3%) Vascularsurgery - total no. (%) 2 (6.3%) 2 (6.6%) Multiple trauma or severeburns - total no. (%) 3 (8.6%) 4 (12.1%) Transplantation - total no. (%)1 (2.3%) 2 (4.3%) Others - total no. (%) 6 (17.1%) 0 (0%) Causes ofdeath during intensive care - total no. 0.02 Multiple organ failure withproven septic focus 33  8 Multiple organ failure, no detectable septicfocus 18 14 Severe brain damage  5  3 Cardiogenic shock  7 10In-hospital deaths - total no. (%) 85 (10.9%) 55 (7.2%) 34 27 0.01In-hospital deaths among patients staying {hacek over (S)} 5 days inICU - total no. (%) 21 (3.9%) 20 (3.6%) = 0.8 In-hospital deaths amongpatients staying >5 days in ICU - total no. (%) 64 (26.3%) 35 (16.8%) 3611 0.01 RRR denotes relative risk reduction. NNT denotes the numberneeded to treat to save one life. P-values were obtainedusing Chi-squaretest.

TABLE 4 Multivariate logistic regression analysis of all baselineunivariate predictors of ICU death Odds Parameter Ratio 95% CI P Age (1added y) 1.03 1.01-1.05 0.002 APACHE II during first 24 h 9 4.922.48-9.78 <0.0001 A non-cardiac surgery type of critical illness 2.241.27-3.97 0.006 Tertiary referral 2.10 1.24-3.56 0.006 A history ofmalignancy 1.47 0.86-2.52 0.2 Admission hyperglycemia 11 mmol/L 1.660.96-2.87 0.07 Intensive Insulin Treatment (IIS) 0.52 0.33-0.82 0.004APACHE denotes Acute Physiology and Chronic Health Evaluation. HigherAPACHE II scores reflect more severe critical illness.

TABLE 5 MORBIDITY ANALYSIS RIS IIS Outcome measure (N = 783) (N = 765)RRR (%) NNT P-value ICU stay Days on ICU (median - IQR) ICU stay {hacekover (S)} 5 days (N = 1097) 2 (2-3) 2 (2-3) 0.2 ICU stay >5 days (N =451) 15 (9-27) 12 (8-20) 0.003 Patients requiring >7 days intensivecare - total no. (%) 206 (26.3%) 157 (20.5%) 22 17 0.007 Patientsrequiring >14 days intensive care - total no. (%) 123 (15.7%) 87 (11.4%)27 23 0.01 Patients requiring >21 days intensive care - total no. (%) 74(9.5%) 50 (6.5%) 32 33 0.03 Mechanical ventilatory support Days onmechanical ventilatory support (median - IQR) ICU stay {hacek over (S)}5 days (N = 1097) 1 (1-2) 1 (1-2) 0.9 ICU stay >5 days (N = 451) 12(7-23) 10 (6-16) 0.006 Patients requiring >7 days ventilatory support -total no. (%) 175 (23.2%) 125 (16.9%) 27 16 0.003 Patients requiring >14days ventilatory support - total no. (%) 93 (12.3%) 57 (7.7%) 37 220.003 Patients requiring >21 days ventilatory support - total no. (%) 62(8.2%) 37 (5.0%) 39 31 0.01 Hemodynamics Patients oninotropic/vasopressor treatment - total no. (%) 586 (75%) 574 (75%) =0.9 Renal function Peak plasma creatinine >2.5 mg/dL - total no. (%) 96(12.2%) 69 (9.0%) 26 31 0.04 Peak plasma urea concentration >150 mg/dL -total no. (%) 88 (11.2%) 59 (7.7%) 31 29 0.02 Patients needing dialysisor CVVH - total no. (%) 64 (8.2%) 37 (4.8%) 42 29 0.007 Liver functionPatients with hyperbilirubinemia (peak bilirubin >2 mg/dL) - total no.(%) 209 (27%) 171 (22%) 19 20 0.04 Infection/Inflammation Patients withblood stream infections during intensive care - total no. (%) 61 (7.8%)32 (4.2%) 46 28 0.003 Patients treated with antibiotics for >10 days -total no. (%) 134 (17.1%) 86 (11.2%) 35 17 0.0009 >3 days C-reactiveprotein level above 150 mg/L -total no. (%) 162 (21%) 119 (15%) 29 170.008 >3 days white blood cell count {hacek over (S)}4000/μL or12000/μL - total no. (%) 166 (21%) 121 (16%) 24 20 0.006 >3 days centralbody temperature {hacek over (S)}36° C. or 38° C. - total no. (%) 206(26%) 164 (21%) 19 20 0.02 Critical illness polyneuropathy Patients withcritical illness polyneuropathy - total no. (% of EMG-screened) 110(52%) 47 (29%) 44 4 <0.0001 Repetitive (>2) positive EMGs - total no. (%of EMG screened) 39 (19%) 11 (7%) 63 8 0.001 Red cell transfusionrequirement Number of patients requiring transfusion - total no. (%) 243(31%) 219 (29%) 0.3 Number of transfusions per patient (median - IQR) 2(1-3) 1 (1-2) 0.0002 Lowest level of hemoglobin (g/dL) when transfused(median - IQR) 8.1 (7.6-8.6) 8.3 (7.7-8.9) 0.02 Lowest level ofhematocrit (%) when transfused (median - IQR) 0.25 (0.24-0.27) 0.26(0.24-0.27) 0.03 Cumulative TISS (median - IQR) ICU stay {hacek over(S)} 5 days (N = 1097) 84 (67-111) 85 (68-115) 0.3 ICU stay >5 days (N =451) 536 (329-956) 431 (271-670) 0.0008 RRR denotes relative riskreduction. NNT denotes the number needed to treat to prevent one patientfrom acquiring the studied complication. EMG denotes electromyographyand CVVH continuous veno-venous hemofiltration. P-values were obtainedusing Mann-Whitney-U test and Chi-square test, when appropriate. Theanalysis of number of transfusions did not take the admission day intoaccount.

1. A method of treating a patient suffering from or at risk of CIPNP,multiple organ failure, need for mechanical ventilatory support, renalreplacement therapy, disturbed kidney function parameters,hyperbilirubinemia, blood stream infections, inflammations and/orinflammatory responses, need for antibiotics, red cell transfusion,stress induced hyperglycaemia, risk of repetitive positive EMGs,cholestasis, or a condition of insulin resistance leading tohyperinsulinimea in combination with hyperglycaemia, comprising treatingsuch a patient with a blood glucose regulator.
 2. The method of claim 1,wherein the blood glucose regulator is insulin, active insulinderivatives, insulin analogues, compounds that stimulate signaltransduction mediated by an insulin receptor type tyrosine kinase in acell, protein-tyrosine phosphatases (PTP's) or other biologically activesubstances having insulin releasing action.
 3. The method of claim 2,wherein the blood glucose regulator is a blood glucose regulator whichis not to be administered orally.
 4. The method of claim 2, wherein theblood glucose regulator is administered to maintain blood glucose levelswithin a range between 60-130 mg/dL.
 5. The method of claim 2, whereinthe blood glucose level is maintained between 80-110 mg/dL.
 6. Themethod of claim 2, wherein the blood glucose level is maintained for 8hours or more.
 7. The method of claim 6, wherein blood glucose level ismaintained for 24 hours or more.
 8. The method of claim 7, wherein bloodglucose level is maintained for 4 days or more.
 9. The method of claim1, wherein the patient is a mammal.
 10. The method of claim 9, whereinthe patient is a human.
 11. The method of claim 10, wherein the patientis non-diabetic.